Pain is a frequent and disabling consequence of metastatic cancer in humans. The cause of this pain is unknown but likely to involve mediator-dependent signaling by tumor cells to nociceptors. The potent vasoactive peptide, endothelin-1 (ET-1), is secreted in high concentrations by metastatic cancer cells and produces pain in animals and in humans. This proposal seeks as its broad long-term objective to understand how tumor mediators cause pain associated with cancer. We have shown that ET-1: 1) induces acute pain behavior and nociceptor excitation via endothelin-A receptors (ETA), 2) mediates mechanical and thermal hyperalgesia in rodent models of skin injury and inflammation, 3) evokes increased Cain2+ , and opening of tetrodotoxin-resistant (TTX-R) Na+ channels in isolated sensory neurons, via ETA, 3) triggers an analgesic cascade in skin, via ETB receptors, that is mediated by locally-released beta-endorphin acting on opioid receptors coupled to G protein inwardly-rectifying K+ channels (GIRKs). The goals of the proposed studies are to combine results from in vitro neurophysiology and pharmacology with neurobehavior to: Specific Aim: 1: Establish that ET-1 initiates impulses in peripheral nociceptors, and identify the changes in ionic (Na+ and K+) currents that underlie this impulse initiation. Specific Aim 2: Establish that ET-1 sensitizes peripheral nociceptors both to the injection of depolarizing current and to the depolarizing actions of both capsaicin and ATP. Specific Aim 3: Determine the ionic basis for inhibitory effects of beta-endorphin on ET-1-induced changes in nociceptor excitability. The findings from these experiments will define the ionic mechanisms whereby ET-1 signals to nociceptors to cause acute and persistent pain, and the ionic mechanisms that underlie inhibitory effects of ETB driven, beta endorphin-mediated inhibition of ET-1-triggered pain. This information should help to identify: 1) new and useful directions for research into mechanisms underlying pain produced by metastatic cancer, and 2) novel targets for drug development aimed at treating this pain.